title: Characterization of hepatitis C virus intra- and intergenotypic chimeras reveals a role of the glycoproteins in virus envelopment.
abstract: Hepatitis C virus (HCV) is highly variable and associated with chronic liver disease. Viral isolates are grouped into seven genotypes (GTs). Accumulating evidence indicates that viral determinants in the core to NS2 proteins modulate the efficiency of virus production. However, the role of the glycoproteins E1 and E2 in this process is currently poorly defined. Therefore, we constructed chimeric viral genomes to explore the role of E1 and E2 in HCV assembly. Comparison of the kinetics and efficiency of particle production by intragenotypic chimeras highlighted core and p7 as crucial determinants for efficient virion release. Glycoprotein sequences, however, had only a minimal impact on this process. In contrast, in the context of intergenotypic HCV chimeras, HCV assembly was profoundly influenced by glycoprotein genes. On the one hand, insertion of GT1a-derived (H77) E1-E2 sequences into a chimeric GT2a virus (Jc1) strongly suppressed virus production. On the other hand, replacement of H77 glycoproteins within the GT1a-GT2a chimeric genome H77/C3 by GT2a-derived (Jc1) E1-E2 increased infectious particle production. Thus, within intergenotypic chimeras, glycoprotein features strongly modulate virus production. Replacement of Jc1 glycoprotein genes by H77-derived E1-E2 did not grossly affect subcellular localization of core, E2, and NS2. However, it caused an accumulation of nonenveloped core protein and increased abundance of nonenveloped core protein structures with slow sedimentation. These findings reveal an important role for the HCV glycoproteins E1 and E2 in membrane envelopment, which likely depends on a genotype-specific interplay with additional viral factors.
authors.affiliation: Institute of Experimental Virology, Twincore, Centre for Experimental and Clinical Infection Research, Medical School Hannover (MHH) and Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
authors.forename: Eike
authors.initials: E
authors.lastname: Steinmann
authors.forename: Juliane
authors.initials: J
authors.lastname: Doerrbecker
authors.forename: Martina
authors.initials: M
authors.lastname: Friesland
authors.forename: Nina
authors.initials: N
authors.lastname: Riebesehl
authors.forename: Corinne
authors.initials: C
authors.lastname: Ginkel
authors.forename: Julia
authors.initials: J
authors.lastname: Hillung
authors.forename: Juliane
authors.initials: J
authors.lastname: Gentzsch
authors.forename: Chris
authors.initials: C
authors.lastname: Lauber
authors.forename: Richard
authors.initials: R
authors.lastname: Brown
authors.forename: Anne
authors.initials: A
authors.lastname: Frentzen
authors.forename: Thomas
authors.initials: T
authors.lastname: Pietschmann
mesh_terms: D002460:Cell Line; D002678:Chimera / Q000145:classification / Q000235:genetics / Q000502:physiology*; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000235:genetics / Q000502:physiology*; D006526:Hepatitis C / Q000821:virology*; D006801:Humans; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism*; D019065:Virus Assembly
chemical_list: C087035:E1 protein, Hepatitis C virus; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus